Charcot-Marie-Tooth type 4B1 (CMT4B1) is a severe autosomal recessive demyelinating neuropathy with childhood onset, caused by loss-of-function mutations in the myotubularin-related 2 (MTMR2) gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3P and PtdIns(3,5)P₂, with a preference for PtdIns(3,5)P₂. A hallmark of CMT4B1 neuropathy are redundant loops of myelin in the nerve termed myelin outfoldings, which can be considered the consequence of altered growth of myelinated fibers during postnatal development. How MTMR2 loss and the resulting imbalance of 3′-phosphoinositides cause CMT4B1 is unknown. Here we show that MTMR2 by regulating PtdIns(3,5)P₂ levels coordinates mTORC1-dependent myelin synthesis and RhoA/myosin II-dependent cytoskeletal dynamics to promote myelin membrane expansion and longitudinal myelin growth. Consistent with this, pharmacological inhibition of PtdIns(3,5)P₂ synthesis or mTORC1/RhoA signaling ameliorates CMT4B1 phenotypes. Our data reveal a crucial role for MTMR2-regulated lipid turnover to titrate mTORC1 and RhoA signaling thereby controlling myelin growth.

Charcot-Marie-Tooth 4B1 型 (CMT4B1) 是一种严重的常染色体隐性脱髓鞘性神经病，儿童发病，由肌管蛋白相关 2 ( MTMR2 ) 基因的功能丧失突变引起。MTMR2 是一种普遍表达的催化活性 3-磷酸酶，它在体外使 3-磷酸肌醇 PtdIns3 P和 PtdIns(3,5) P ₂去磷酸化，优先选择 PtdIns(3,5) P ₂. CMT4B1 神经病的一个标志是神经中多余的髓鞘环，称为髓鞘外折叠，这可以被认为是出生后发育过程中髓鞘纤维生长改变的结果。MTMR2 丢失和由此产生的 3'-磷酸肌醇失衡如何导致 CMT4B1 尚不清楚。在这里，我们显示 MTMR2 通过调节 PtdIns(3,5) P ₂水平协调 mTORC1 依赖性髓鞘合成和 RhoA/肌球蛋白 II 依赖性细胞骨架动力学，以促进髓鞘膜扩张和纵向髓鞘生长。与此一致，PtdIns(3,5) P _{2 的}药理抑制合成或 mTORC1/RhoA 信号改善 CMT4B1 表型。我们的数据揭示了 MTMR2 调节的脂质周转对滴定 mTORC1 和 RhoA 信号从而控制髓鞘生长的关键作用。